The behavioral pharmacological profile of a drug in a pertinent species is necessary for evaluating quantitatively not only how the drug functions as a reinforcer but also how use or abuse of the drug affects other aspects of the subjects behavior. Ongoing studies on the direct behavioral effects of drugs include a number of different paradigms. A variety of studies involve observations of changes in spontaneous and learned behavior following acute injections of drugs. For example, we have recently shown that female rats are more sensitive to the locomotor activating effects of cocaine than are male rats. This effect does not appear to be due to any differences in the genders ability to metabolize the drug. Recent research has shown that male and female rats also differ in their response to methamphetamine. Therefore, this gender-specific effect of an abused drug may have wide generality. A wide range of other studies are ongoing to investigate pharmacological mechanisms that determine how psychoactive drugs such as nicotine, methamphetamine, and cocaine function as discriminative stimuli or effect ongoing learned behavior. In one series of studies we are using laboratory animals to characterize nicotine-caffeine interactions under conditions of chronic caffeine exposure. There is a strong positive correlation between coffee drinking and cigarette smoking and these studies are designed to determine if caffeine-nicotine interactions can be observed in animals. For these studies, rats were chronically exposed to caffeine in their drinking water. Then the behavioral responses to nicotine, as well as to amphetamine and cocaine, were compared in these caffeinated rats to responses in water-drinking control rats. Our studies revealed that chronic caffeine exposure modifies the behavioral effects of nicotine, amphetamine and cocaine. Both caffeine concentration and the duration of caffeine exposure appeared to be critical in these effects. Chronic caffeine exposure appeared to specifically alter the dopaminergic component of nicotines actions. In other studies we extensively investigated the pharmacological properties of methamphetamine discrimination in rats and squirrel monkeys. We have found that dopaminergic neurotransmission plays the crucial role in methamphetamines discriminative-stimulus effects. Different dopamine-uptake inhibitors and agonists at different dopaminergic receptors fully substituted for methamphetamine in this study. However, other non-dopaminergic mechanisms contribute as well. Both serotonin and norepinephrine-uptake inhibitors markedly potentiate methamphetamines effects. Serotonergic modulation appears to be mediated predominantly by 5-HT2A/2C receptors, whereas noradrenergic modulation by alpha-2 receptors. Finally, we have found that selegiline, a potential medication for cocaine abuse, has cocaine- and methamphetamine-like discriminative stimulus which are due to its conversion to active methamphetamine-like metabolites. - drug discrimination, schedule-controlled behavior, locomotor activitiy, methamphetamine, nicotine, cocaine, rats